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Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agoni

Abstract
Purpose Positron emission tomography (PET) imaging ofserotonin 2A (5-HT2A) receptors with agonist tracers holds
promise for the selective labelling of 5-HT2A receptors in their
high-affinity state. We have previously validated [11C]Cimbi-5
and found that it is a 5-HT2A receptor agonist PET tracer. In an
attempt to further optimize the target-to-background binding
ratio, we modified the chemical structure of the phenethylamine
backbone and carbon-11 labelling site of [11C]Cimbi-5
in different ways. Here, we present the in vivo validation of nine
novel 5-HT2A receptor agonist PET tracers in the pig brain.
Methods Each radiotracer was injected intravenously into
anaesthetized Danish Landrace pigs, and the pigs were
subsequently scanned for 90 min in a high-resolution
research tomography scanner. To evaluate 5-HT2A receptor
binding, cortical nondisplaceable binding potentials (BPND)
were calculated using the simplified reference tissue model
with the cerebellum as a reference region.
Results After intravenous injection, all compounds entered
the brain and distributed preferentially into the cortical
areas, in accordance with the known 5-HT2A receptor
distribution. The largest target-to-background binding ratio
was found for [11C]Cimbi-36 which also had a high brain
uptake compared to its analogues. The cortical binding of
[11C]Cimbi-36 was decreased by pretreatment with ketanserin,
supporting 5-HT2A receptor selectivity in vivo. [11C]
Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND,
while [11C]Cimbi-27, [11C]Cimbi-29, [11C]Cimbi-31 and
[11C]Cimbi-88 gave rise to cortical BPND similar to that of
[11C]Cimbi-5.
Conclusion [11C]Cimbi-36 is currently the most promising
candidate for investigation of 5-HT2A receptor agonist
binding in the living human brain with PET.